Human and animal studies show that females are more susceptible to drug addiction than males. The hormone estrogen appears to interact with underlying sexual dimorphism in addiction-related neural circuitry to produce females'greater susceptibility to addictive drugs. The nucleus accumbens is central in the neural circuitry of addiction, and chronic exposure to drugs such as cocaine produces persistent increases in dendritic length and dendritic spine density on accumbens neurons. These drug-induced dendritic changes suggest alterations in synaptic connectivity of the nucleus accumbens that could be related to the process of addiction, but this has never been tested directly. Furthermore, analogy to estrogen's effects on dendritic spines and synapses in the hippocampus suggests that estrogen might potentiate drug-induced dendritic changes in females, which could contribute to their greater susceptibility to addiction. However, whether cocaine-induced dendritic and synaptic changes in the nucleus accumbens occur differently in males and females has never been tested. We will use a combination of light and electron microscopy, western blotting, and whole-cell patch camp electrophysiology in rats to investigate whether and how chronic cocaine-induced changes in the dendritic arbor of nucleus accumbens neurons are paralleled by synaptic changes, and whether and how such dendritic/synaptic changes occur differently in males and females. There are 3 specific aims: 1) Use c-Fos, FosB, deltaFosB, and P-CREB immunostaining and western blots to map cocaine-responsive subregions of nucleus accumbens in male and female rats;2) Use whole-cell patch clamp recording to determine the effect(s) of chronic cocaine exposure on functional synaptic connectivity in the nucleus accumbens of male and female rats;3) Use light and electron microscopy to determine the effect(s) of chronic cocaine exposure on structural synaptic connectivity in the nucleus accumbens of male and female rats. These studies will determine whether chronic exposure to drugs of abuse such as cocaine produces long- lasting changes in the structure and/or function of addiction-related brain circuitry, and whether drug-induced changes in the structure and function of addiction-related brain circuitry differ between males and females. The results will contribute to an understanding of gender differences in drug addiction.